When is a seamless study desirable? Case studies from different pharmaceutical sponsors.

BACKGROUND: Inferentially seamless studies are one of the best-known adaptive trial designs. Statistical inference for these studies is a well-studied problem. Regulatory guidance suggests that statistical issues associated with study conduct are not as well understood. Some of these issues are caused by the need for early pre-specification of the phase III design and the absence of sponsor access to unblinded data. Before statisticians decide to choose a seamless IIb/III design for their programme, they should consider whether these pitfalls will be an issue for their programme.
METHODS: We consider four case studies. Each design met with varying degrees of success. We explore the reasons for this variation to identify characteristics of drug development programmes that lend themselves well to inferentially seamless trials and other characteristics that warn of difficulties.
RESULTS: Seamless studies require increased upfront investment and planning to enable the phase III design to be specified at the outset of phase II. Pivotal, inferentially seamless studies are unlikely to allow meaningful sponsor access to unblinded data before study completion. This limits a sponsor's ability to reflect new information in the phase III portion.
CONCLUSIONS: When few clinical data have been gathered about a drug, phase II data will answer many unresolved questions. Committing to phase III plans and study designs before phase II begins introduces extra risk to drug development. However, seamless pivotal studies may be an attractive option when the clinical setting and development programme allow, for example, when revisiting dose selection.